P2‐445: Quantification of Beta‐amyloid Ï€ Peptides in Dog CSF Following Gamma‐secretase Modulator and Inhibitor Treatment

The g-secretase complex generates the C-terminus of Aß from APP and thus determines the potential for oligomerization, formation and propensity for deposition. Inhibition of g-secretase activity blocks Aß production and is being tested as disease modifying treatment for AD. However, g-secretase inhibitors (GSIs) also block the cleavage of other g-secretase substrates such as Notch, which can lead to gastrointestinal and immune related toxicity. g-secretase modulators (GSMs), on the other hand, reduce specifically the formation of Aß42, without affecting the signaling functions of other g-secretase substrates. This selective reduction of Aß42 levels after GSM treatment is accompanied by an increase in the production of the shorter and less toxic Aß species. We investigate the effect of GSMs and GSIs on Aß levels in cerebrospinal fluid (CSF) from beagle dogs and utilize specific and sensitive immunoassays for the quantification of Aß species of different lengths. We show that GSM treatment leads to decreased levels of Aß42 and increased levels of shorter Aß peptides in dog CSF. Our data support that quantification of shorter Aß peptides can be used as a pharmacodynamic marker of GSM treatment. As expected, the results show that GSIs are able to decrease the levels of all Aß peptides in dog CSF. We have produced highly sensitive and specific assays that can detect Aß species in dog CSF. Our data show that GSMs are able to selectively reduce the levels of the Aß42 toxic species and increase the levels of shorter Aß species, thus representing a promising approach for a disease-modifying treatment of AD.